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Found 34725 matches. Displaying 111-120
Lama L, Adura C, Xie W, Tomita D, Kamei T, Kuryavyi V, Gogakos T, Steinberg JI, Miller M, Ramos-Espiritu L, Asano Y, Hashizume S, Aida J, Imaeda T, Okamoto R, Jennings AJ, Michino M, Kuroita T, Stamford A, Gao P, Meinke P, Glickman JF, Patel DJ, Tuschl T
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Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression

NATURE COMMUNICATIONS 2019 MAY 21; 10(?):? Article 2261
Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.
Weisenburger S, Tejera F, Demas J, Chen B, Manley J, Sparks FT, Traub FM, Daigle T, Zeng HK, Losonczy A, Vaziri A
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Volumetric Ca2+ Imaging in the Mouse Brain Using Hybrid Multiplexed Sculpted Light Microscopy

CELL 2019 MAY 2; 177(4):1050-1066.e14
Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 x 1 x 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.
Ellis SJ, Gomez NC, Levorse J, Mertz AF, Ge YJ, Fuchs E
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Distinct modes of cell competition shape mammalian tissue morphogenesis

NATURE 2019 MAY 23; 569(7757):497-502
Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imaging, lineage tracing, single-cell transcriptomics and genetics, we identify two cell competition mechanisms that sequentially shape and maintain the architecture of stratified tissue during skin development in mice. In the single-layered epithelium of the early embryonic epidermis, winner progenitors kill and subsequently clear neighbouring loser cells by engulfment. Later, as the tissue begins to stratify, the basal layer instead expels losers through upward flux of differentiating progeny. This cell competition switch is physiologically relevant: when it is perturbed, so too is barrier formation. Our findings show that cell competition is a selective force that optimizes vertebrate tissue function, and illuminate how a tissue dynamically adjusts cell competition strategies to preserve fitness as its architectural complexity increases during morphogenesis.
Araya-Salas M, Smith-Vidaurre G, Mennill DJ, Gonzalez-Gomez PL, Cahill J, Wright TF
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Social group signatures in hummingbird displays provide evidence of co-occurrence of vocal and visual learning

Vocal learning, in which animals modify their vocalizations based on social experience, has evolved in several lineages of mammals and birds, including humans. Despite much attention, the question of how this key cognitive trait has evolved remains unanswered. The motor theory for the origin of vocal learning posits that neural centres specialized for vocal learning arose from adjacent areas in the brain devoted to general motor learning. One prediction of this hypothesis is that visual displays that rely on complex motor patterns may also be learned in taxa with vocal learning. While learning of both spoken and gestural languages is well documented in humans, the occurrence of learned visual displays has rarely been examined in non-human animals. We tested for geographical variation consistent with learning of visual displays in long-billed hermits (Phaethornis longirostris), a lek-mating hummingbird that, like humans, has both learned vocalizations and elaborate visual displays. We found lek-level signatures in both vocal parameters and visual display features, including display element proportions, sequence syntax and fine-scale parameters of elements. This variation was not associated with genetic differentiation between leks. In the absence of genetic differences, geographical variation in vocal signals at small scales is most parsimoniously attributed to learning, suggesting a significant role of social learning in visual display ontogeny. The co-occurrence of learning in vocal and visual displays would be consistent with a parallel evolution of these two signal modalities in this species.
Morley-Fletcher S, Mairesse J, Van Camp G, Reynaert ML, Gatta E, Marrocco J, Bouwalerh H, Nicoletti F, Maccari S
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Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle

Stress and the circadian systems play a major role in an organism's adaptation to environmental changes. The adaptive value of the stress system is reactive while that of the circadian system is predictive. Dysfunctions in these two systems may account for many clinically relevant disorders. Despite the evidence that interindividual differences in stress sensitivity and in the functioning of the circadian system are related, there is limited integrated research on these topics. Moreover, sex differences in these systems are poorly investigated. We used the perinatal stress (PRS) rat model, a well-characterized model of maladaptive programming of reactive and predictive adaptation, to monitor the running wheel behavior in male and female adult PRS rats, under a normal light/dark cycle as well as in response to a chronobiological stressor (6-h phase advance/shift). We then analyzed across different time points the expression of genes involved in circadian clocks, stress response, signaling, and glucose metabolism regulation in the suprachiasmatic nucleus (SCN). In the unstressed control group, we found a sex-specific profile that was either enhanced or inverted by PRS. Also, PRS disrupted circadian wheel-running behavior by inducing a phase advance in the activity of males and hypoactivity in females and increased vulnerability to chronobiological stress in both sexes. We also observed oscillations of several genes in the SCN of the unstressed group in both sexes. PRS affected males to greater extent than females, with PRS males displaying a pattern similar to unstressed females. Altogether, our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.
Prakash V, Carson BB, Feenstra JM, Dass RA, Sekyrova P, Hoshino A, Petersen J, Guo Y, Parks MM, Kurylo CM, Batchelder JE, Haller K, Hashimoto A, Rundqivst H, Condeelis JS, Allis CD, Drygin D, Nieto MA, Andang M, Percipalle P, Bergh J, Adameyko I, Farrants AKO, Hartman J, Lyden D, Pietras K, Blanchard SC, Vincent CT
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Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

NATURE COMMUNICATIONS 2019 MAY 8; 10(?):? Article 2110
Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
Kerner G, Ramirez-Alejo N, Seeleuthner Y, Yang R, Ogishi M, Cobat A, Patin E, Quintana-Murci L, Boisson-Dupuis S, Casanova JL, Abel L
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Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in similar to 1/600 Europeans and similar to 1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 x 10(-3)]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for similar to 1% of TB cases in Europeans.
Brodmerkel C, Li K, Garcet S, Hayden K, Chiricozzi A, Novitskaya I, Fuentes-Duculan J, Suarez-Farinas M, Campbell K, Krueger JG
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Modulation of inflammatory gene transcripts in psoriasis vulgaris: Differences between ustekinumab and etanercept

Miao YX, Yang HS, Levorse J, Yuan SP, Polak L, Sribour M, Singh B, Rosenblum MD, Fuchs E
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Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells

CELL 2019 MAY 16; 177(5):1172-1186.e14
Our bodies are equipped with powerful immune surveillance to clear cancerous cells as they emerge. How tumor-initiating stem cells (tSCs) that form and propagate cancers equip themselves to overcome this barrier remains poorly understood. To tackle this problem, we designed a skin cancer model for squamous cell carcinoma (SCC) that can be effectively challenged by adoptive cytotoxic T cell transfer (ACT)-based immunotherapy. Using single-cell RNA sequencing (RNA-seq) and lineage tracing, we found that transforming growth factor beta (TGF-beta)-responding tSCs are superior at resisting ACT and form the root of tumor relapse. Probing mechanism, we discovered that during malignancy, tSCs selectively acquire CD80, a surface ligand previously identified on immune cells. Moreover, upon engaging cytotoxic T lymphocyte antigen-4 (CTLA4), CD80-expressing tSCs directly dampen cytotoxic T cell activity. Conversely, upon CTLA4- or TGF-beta-blocking immunotherapies or Cd80 ablation, tSCs become vulnerable, diminishing tumor relapse after ACT treatment. Our findings place tSCs at the crux of how immune checkpoint pathways are activated.